Adult human islets proliferate when cultured using purified laminin-5 extracellular matrix. This ability to proliferate adult human islets ex-vivo has direct potential application to the treatment of diabetes through transplantation, but more importantly, readily allows the mechanisms of adult human islet proliferation to be studied. Understanding the processes occurring when islets expand in culture may lead to novel treatments to restore an adequate beta cell mass in diabetic patients. The overall objective of this research proposal is to understand the mechanisms leading to the ex vivo proliferation of adult human islets. The specific aims are as follows: 1) Determine fully the sequence of morphological and functional phenotype changes that occur when adult human islets proliferate in culture. 2) Determine the factors controlling the phenotype changes and regulating ex vivo adult human islet proliferation. Recently several gene transcription factors that control islet hormone production have in addition been found to play critical roles in the development of the pancreas. The proposed experiments are particularly focused on these transcription factors because they are very likely to be regulated during adult human islet proliferation in culture. To accomplish these objectives adult human islets will be proliferated ex vivo, and examined using cellular and molecular methods.